This collaborative application proposes a controlled trial of a tiered substance use prevention program with the Project Success (PS) intervention approach. The PS approach, based on having trained masters-level counselors in schools to deliver prevention services, is widely used but has not been tested with a controlled evaluation. The research will involve implementing a tiered prevention program beginning in middle schools and following participants into high school. The program will have a universal component delivered to all students in the school, and a selected intervention for students at higher risk for substance use. Program effectiveness will be tested with a matched sample of 5 program schools and 5 comparison schools. Participants will be followed with yearly assessments over a 5-year period. Outcome variables will include measures of usage frequency and problem use for tobacco, alcohol, marijuana, and unauthorized prescription drug use;and measures of related problem behaviors (aggression, depression, problem gambling, risky driving, and sexual behavior). Program effectiveness will be analyzed with multilevel ANOVA models and latent growth models to determine program impact on growth in substance use and related behaviors over time. Propensity scores will be utilized to control for any baseline differences. The research will incorporate behavioral and emotional self-control concepts in the evaluation so as to gain information about process variables in program effects. Analyses will incorporate indices of program dosage and implementation fidelity in the evaluation using the compier average causal effect (CACE) estimation approach. Structural equation modeling will test for mediation of program effects through self-control and other constructs, and multilevel ANOVA models will test for moderation of program effects by gender and problem behavior level. Exploratory analyses will study variables that predict which students seek help for substance use problems. The findings will have implications for school-based programs to prevent substance use and comorbid problems. Adolescent tobacco and alcohol use, particularly use that begins early, are related to several diseases in adulthood. Preventing substance use and abuse in adolescence thus is relevant for the health of the population, but few programs have been designed to address substance abuse and comorbid mental health problems in adolescence. The present study addresses this goal by providing a two-level intervention aimed at prevention of both substance use onset and transition to substance abuse in a general population of adolescents, beginning in middle school and continuing into the high school years.